Mutant-bearing stocks of rabbits are valuable models of human constitutional diseases. We propose to investigate one such model in depth. Buphthalmia (bu/bu) in the rabbit is similar to human congenital glaucoma. Our overall approach is to define the glaucomatous-like changes associated with this animal model developmentally, compared with genetically related controls using both morphological and biochemical criteria. Glaucomatous lesions have been observed at birth using histological techniques. Therefore, we will investigate the prenatal and postnatal development of glaucoma in the rabbit. Recent analyses of serum and aqueous humor revealed marked reductions in aqueous humor ascorbate levels associated with progressive stages of glaucoma and a differential fluid transport rate associated with the bu/bu genotype when ascorbate was given intravenously to lower the intraocular pressure in both normal and glaucomatous rabbits. We propose to analyze both serum and aqueous humor for these and other biochemical variants and their relationship to buphthalmia. We propose to determine the circadian rhythm of both intraocular pressure and steroid levels in normal and buphthalmic rabbits. The numerous effects of the bu gene are similar to the pathological conditions associated with vitamin A deficiency. We will analyze the long-term effects of vitamin A and its precursor, beta-carotene, on the genetic penetrance and expressivity of the bu gene in order to determine a therapeutic regimen for preventing its consequences. We also propose to determine the mode of inheritance and the pleiotropic effects of phenotypic deviants, particularly ocular variants, in the rabbit stocks to provide a source of material for future research proposals. We will also encourage and continue collaborative research investigating the etiology of the pathologies observed with specific mutations such as buphthalmia.